During the past 25 years, embryonic and early fetal ultrasound and diagnosis have increasingly gained attention in pregnancy care. Modern high-frequency ultrasound transducers make it possible to obtain detailed images of the early conceptus and its organs, and thus move part of the anatomy and anomaly scan from the second to the first trimester. Today, detection of embryonic and fetal structural abnormalities in the first trimester has frequently been reported. One has to distinguish between diagnosis during the early period until about 10 weeks when the embryo or early fetus is small and transvaginal ultrasound is applied, and diagnosis during the late period at the nuchal translucency screening, usually carried out using transabdominal ultrasound. Early first-trimester abnormalities are often diagnosed by chance on clinical indications, whereas late first-trimester diagnoses are the result of systematic screening using ultrasound markers.
Introduction
The aims of any early pregnancy ultrasound scan should be to determine viability and age of the embryo or fetus, to detect multiples and describe chorionicity and amnionicity, and to detect gross abnormalities. At 10 postmenstrual weeks, an embryo is less than one-half the length of an adult thumb, but possesses already several thousands of identified structures, practically any of which may be subject to developmental deviations . Holoprosencephaly, for example, develops early in embryonic life, and has been diagnosed by light-microscope in 201 cases of 44,000 early pregnancy terminations and miscarriages before 10 weeks . Thus, the embryonic period proper is of importance because most congenital anomalies make their appearance during that time, and it should be possible to detect major structural anomalies by ultrasound.
Over the past 25 years, embryonic and early fetal ultrasound and diagnosis has gained increased attention in pregnancy care. It started with the general introduction of transvaginal ultrasound transducers, which by its improved resolution made it possible to develop the research field ‘sonoembryology’ . At the same time, the first first-trimester diagnoses of structural anomalies were reported .
When we talk about detection of first-trimester structural abnormalities, the definition of gestational age is important: a trimester corresponds to a period of 3 months, and trimesters are used to divide pregnancies into three periods of approximately equal length. An exact definition of the transition between the trimesters is not possible, because no specific developmental stages would indicate such borders . The introduction of the 11–13+6 weeks scan has established a practical break of the end of the first trimester at 13+6 to 14+0 weeks. In addition, we have to make a distinction between diagnoses made during the 11–13+6 week scan in a screening situation, and those made before this period during the embryonic period on clinical indications. The prerequisite for any early diagnosis and the understanding of how and when anomalies can be detected later in pregnancy is the knowledge of the normal development of the human embryo and the corresponding sonographic appearance . The transvaginal approach should be preferred for examinations before 11–12 weeks gestation.
In this chapter, we present an overview of normal development and review the relevant literature on early diagnoses of structural abnormalities. All statements of gestational age are based on the last menstrual period, expressed in completed weeks and completed days, assuming a regular cycle with ovulation at 2 weeks 0 days.
Normal development in the first trimester
The human embryo develops from the fertilised ovum, through the bilaminar and three-laminar disc, into a cylindrical body, and only at the end of the embryonic period does it look like an immature human being. Except for the physiological herniation of bowel into the umbilical coelom from 7–11 weeks, the body wall is already established after the folding process during weeks 4 and 5.
Measurement of the conceptus is important, because healthy embryos and their associated structures, such as the amniotic cavity, show virtually identical growth velocities . In addition, embryos of the same size (crown-lump length [CRL]) look identical. The development of the size of embryos and the shape of the body and the brain cavities are in accordance with images from the embryological literature . All these facts can be used as the basis for early sonographic assessment. The synopsis in Table 1 shows the normal development of the embryo based on sonoanatomic descriptions of longitudinal two-dimensional studies and on three-dimensional ultrasound studies week by week ( Table 1 ) .
| Age | CRL | Sonoanatomical development and visible structures |
|---|---|---|
| 4 weeks 0–6 days | At 4.5 weeks tiny gestational sac (diameter 2 mm). | |
| 5 weeks 0–6 days | 0–3 mm | Yolk sac: at 5.5 weeks embryonic pole adjacent to yolk sac; heart activity 80–100 bpm. |
| 6 weeks 0–6 days | 4–9 mm | Embryo, yolk sac, heart rate 100–130 bpm; shallow rhombencephalic cavity at top of the head. |
| 7 weeks 0–6 days | 9–14 mm | In the sagittal section, the embryonic body appears as a triangle. The sides consist of the back, the roof of the rhombencephalon, and the frontal part includes of the head, the basis of the umbilical cord, and the embryonic tail. The embryonic body is slender in the coronal plane. Lateral ventricles, third ventricle, aqueduct and fourth ventricle; spine appears as two lines; heart rate 130–160 bpm; first sign of limbs; physiological mid-gut herniation begins; amniotic membrane surrounds embryo, yolk sac in chorionic cavity. |
| 8 weeks 0–6 days | 15–22 mm | Choroid plexuses visible in lateral ventricles and fourth ventricle; third ventricle and Sylvian aqueduct are wide; heart chambers visible, atria wider than ventricles; heart rate 160–180 bpm; fluid in stomach; limbs visible; and small cysts in umbilical cord are common at 8 and 9 weeks. |
| 9 weeks 0–6 days | 23–31 mm | Ellipsoid shape of embryonic body and large head. It is possible to obtain acceptable images of embryonic profile. Cerebral hemispheres are C-shaped, third ventricle becomes narrower, Sylvian aqueduct wide, deeper third ventricle (flection of brain), echogenic choroid plexuses traverse roof of fourth ventricle; eyes are visible; ossification of clavicle, mandible and maxilla; oesophagus presents as bright line behind the heart; heart rate mean 175 bpm; stomach; large physiologic herniation; fingertips meet in the midline in front of the chest, feet are still supinated; possible to identify fingers and toes. |
| 10–11 weeks | 32–54 mm | Fetal period begins: fetus has developed human appearance; head still relatively large; large cerebral hemispheres dominate the brain; narrow second ventricle, large Sylvian aqueduct, choroid plexuses of fourth ventricle close to cerebellar hemispheres; oesophagus presents as double line; heart chambers, valves, crux of the heart and large vessels can be identified in increasing number of cases; heart rate mean 165 bpm; physiological mid-gut herniation very large at 10 weeks, bowel returned to abdominal cavity before 12 weeks/CRL 50 mm; relatively bright kidneys and tiny fluid filled urinary bladder; indifferent genital tubercle. |
| 12–13 weeks | 55–84 mm | Corpus callosum begins to develop, small cavum septi pellucidi in some cases at the end of first trimester; external gender definitively developed at CRL ≥ 69 mm or BPD ≥ 23 mm . |
a The embryonic period lasts approximately until the end of week 9, and the fetal period begins at 10 weeks. CRL. Crown–rump length; BPD, biparietal diameter.
Normal development in the first trimester
The human embryo develops from the fertilised ovum, through the bilaminar and three-laminar disc, into a cylindrical body, and only at the end of the embryonic period does it look like an immature human being. Except for the physiological herniation of bowel into the umbilical coelom from 7–11 weeks, the body wall is already established after the folding process during weeks 4 and 5.
Measurement of the conceptus is important, because healthy embryos and their associated structures, such as the amniotic cavity, show virtually identical growth velocities . In addition, embryos of the same size (crown-lump length [CRL]) look identical. The development of the size of embryos and the shape of the body and the brain cavities are in accordance with images from the embryological literature . All these facts can be used as the basis for early sonographic assessment. The synopsis in Table 1 shows the normal development of the embryo based on sonoanatomic descriptions of longitudinal two-dimensional studies and on three-dimensional ultrasound studies week by week ( Table 1 ) .
| Age | CRL | Sonoanatomical development and visible structures |
|---|---|---|
| 4 weeks 0–6 days | At 4.5 weeks tiny gestational sac (diameter 2 mm). | |
| 5 weeks 0–6 days | 0–3 mm | Yolk sac: at 5.5 weeks embryonic pole adjacent to yolk sac; heart activity 80–100 bpm. |
| 6 weeks 0–6 days | 4–9 mm | Embryo, yolk sac, heart rate 100–130 bpm; shallow rhombencephalic cavity at top of the head. |
| 7 weeks 0–6 days | 9–14 mm | In the sagittal section, the embryonic body appears as a triangle. The sides consist of the back, the roof of the rhombencephalon, and the frontal part includes of the head, the basis of the umbilical cord, and the embryonic tail. The embryonic body is slender in the coronal plane. Lateral ventricles, third ventricle, aqueduct and fourth ventricle; spine appears as two lines; heart rate 130–160 bpm; first sign of limbs; physiological mid-gut herniation begins; amniotic membrane surrounds embryo, yolk sac in chorionic cavity. |
| 8 weeks 0–6 days | 15–22 mm | Choroid plexuses visible in lateral ventricles and fourth ventricle; third ventricle and Sylvian aqueduct are wide; heart chambers visible, atria wider than ventricles; heart rate 160–180 bpm; fluid in stomach; limbs visible; and small cysts in umbilical cord are common at 8 and 9 weeks. |
| 9 weeks 0–6 days | 23–31 mm | Ellipsoid shape of embryonic body and large head. It is possible to obtain acceptable images of embryonic profile. Cerebral hemispheres are C-shaped, third ventricle becomes narrower, Sylvian aqueduct wide, deeper third ventricle (flection of brain), echogenic choroid plexuses traverse roof of fourth ventricle; eyes are visible; ossification of clavicle, mandible and maxilla; oesophagus presents as bright line behind the heart; heart rate mean 175 bpm; stomach; large physiologic herniation; fingertips meet in the midline in front of the chest, feet are still supinated; possible to identify fingers and toes. |
| 10–11 weeks | 32–54 mm | Fetal period begins: fetus has developed human appearance; head still relatively large; large cerebral hemispheres dominate the brain; narrow second ventricle, large Sylvian aqueduct, choroid plexuses of fourth ventricle close to cerebellar hemispheres; oesophagus presents as double line; heart chambers, valves, crux of the heart and large vessels can be identified in increasing number of cases; heart rate mean 165 bpm; physiological mid-gut herniation very large at 10 weeks, bowel returned to abdominal cavity before 12 weeks/CRL 50 mm; relatively bright kidneys and tiny fluid filled urinary bladder; indifferent genital tubercle. |
| 12–13 weeks | 55–84 mm | Corpus callosum begins to develop, small cavum septi pellucidi in some cases at the end of first trimester; external gender definitively developed at CRL ≥ 69 mm or BPD ≥ 23 mm . |
a The embryonic period lasts approximately until the end of week 9, and the fetal period begins at 10 weeks. CRL. Crown–rump length; BPD, biparietal diameter.
Structural abnormalities during embryonic period
There are many clinical indications for an early ultrasound examination, such as threatened abortions (e.g. bleeding, pain), suspicion of ectopic pregnancy, uncertain pregnancy length, survey after assisted fertilisation, and targeted examination of anatomy because of maternal disease (e.g. diabetes), hereditary disease, known exposition to teratogens (e.g. anti-epileptica and lithium), and previous pregnancy with fetal anomaly. The patient-in-the-patient (the embryo), is the centre of attention. The sonographer’s professional aim should be to diagnose abnormal development, if it is present, to prevent unnecessary harm to the woman, embryo or fetus. Any significant deviation from the developmental schedule described in Table 1 , including abnormal biometry, can be the expression of a structural abnormality.
All first-trimester miscarriages usually show sonographic abnormalities, such as the yolk sac being too large or too small, the amniotic cavity being too large, or the embryonic pole being too small, abnormal, or the heart rate being too slow. Of interest, are those abnormalities in which the embryo continues to live and develop. In such cases, we might expect the following ultrasound findings: abnormal contours of head, body wall and limbs; abnormal decrease in fluid amount in brain cavities; abnormal increase in fluid amount in brain cavities, thorax, abdomen, and intestinal tract; abnormal number of limbs, fingers and toes; and abnormal biometry of CRL, biparietal diameter (BPD), heart rate, amniotic cavity, and yolk sac.
By looking at the embryo and keeping these guidelines in mind, one should be able to detect embryos with major anomalies where survival into the fetal period or even until and after birth is possible.
Central nervous system anomalies
Most embryonic and fetal diagnoses must be expected from the developing central nervous system because it is the most impressive organ system of the embryo and fetus . It is not surprising that the first report of a first-trimester ultrasound diagnosis was an anencephaly , 25 years after its earliest description in the third trimester . The abnormal shape of the head in this condition is relatively easy to detect. In such a fetus, where the CRL and BPD cannot be normal, the abdominal diameter will represent a useful biometric parameter. In acrania (exencephaly), only a thin layer, if any, covers the brain. Ultrasound images usually show an abnormally shaped cephalic pole . In our experience, the striking feature of acrania at 8–9 weeks gestation is the altered appearance of the brain cavities with decreased fluid content . If one consequently measures the head width (BPD), one cannot overlook serious brain defects.
Both neural tube defects and the amniotic rupture sequence may develop into an encephalocele. Occipital encephalocele, caused by amniotic rupture sequence, was described in a 9-week-old embryo . An irregular protrusion at the posterior part of the head was found. In addition, it was not possible to identify the brain cavities, as they were empty .
Encephalocele is also a well-known part of the Meckel–Gruber syndrome. In two cases of Meckel–Gruber syndrome at 8 weeks, an encephalocele was not seen, but the cavity of the rhombencephalon was enlarged . In another 9-week 0 day-old embryo (CRL 22 mm), a dysraphic defect at the occiput and a significantly enlarged rhombencephalic cavity were demonstrated . The additional finding of polydactyly helped to diagnose Meckel–Gruber syndrome . Thus, it seems that the occipital encephalocele in Meckel–Gruber syndrome becomes visible at the end of the embryonic and early fetal period. Encephalocele may also be associated with other inherited conditions. In a case of cerebro–oculo–muscular–syndrome, a significant protrusion of the mesencephalic roof could be shown at 10.5 weeks, which successively developed into an encephalocele during the following weeks .
Holoprosencephaly is a heterogeneous entity of central nervous system anomalies that results from a primary defect in induction and patterning of the rostral neural tube (basal forebrain). This defect leads to varying degrees of incomplete separation of the cerebral hemispheres and facial anomalies. Holoprosencephaly is graded according to the severity of the brain anomaly as alobar, semi-lobar, lobar and middle interhemispheric variant . The development of the telencephalon into cerebral hemispheres becomes visible during week 7. Thus, the diagnosis of alobar holoprosencephalon can be expected at 8 weeks.
Spina bifida can be detected during the embryonic period at 9 weeks, as described in a case series in 2000 . The sonographic appearance of bifid spine in embryos is a significant irregularity of the contours of the spine and back . The detection of such an embryonic or fetal malformation is usually made by two-dimensional ultrasound, but three-dimensional ultrasound may enhance the abnormality ( Fig. 1 ). Another recent case report using two-and three-dimensional ultrasound showed a large cystic structure at the caudal part of the spine representing a large myelomeningocele .
Facial anomalies
At the end of the embryonic period, the eyes, the maxille, and the mandible are identifiable. Major anomalies that involve these structures should be detectable as shown in a case with amniotic rupture sequence . The typical facial anomalies associated with alobar holoprosencephaly, such as proboscis and extreme hypotelorism or cyclopia have been diagnosed by ultrasound in the embryonic period . Anyplane slicing in the three-dimensional mode helped to enhance imaging of hypotelorism . An example of van der Woude syndrome with bilateral cleft lip and palate was described in a 10-week, 3 day-old fetus .
Heart anomalies
So far, a complete and detailed diagnosis of complicated heart defects is reserved for the end of the first and the second trimester.
Body wall defects
Because of the physiological “abdominal wall defect” that is clearly visible by ultrasound until 10–11 weeks, we have to be cautious in making diagnoses such as omphalocele before 12 weeks. The normal size and development of the physiological mid-gut herniation is described longitudinally from 7–12 weeks , and may aid in differentiating normal and abnormal body wall development. Contemplations about the pathogenesis of body wall defects tend to categorise these defects according to their location in relationship to the umbilicus . We may divide the ventral wall defects into cranial defects (e.g. ectopia cordis, Cantrell’s pentalogy, and epigastric omphalocele); central defects (e.g. central omphalocele, gastroschisis); caudal defects (e.g. bladder exstrophy, cloacal exstrophy, omphalocele-exstrophy-imperforate anus-spinal defects complex); and complex defects (e.g. limb–body–wall–complex), including body stalk anomaly, and body wall defect caused by amniotic rupture sequence .
Before 12 weeks gestation, differentiation by ultrasound according to these sub-groups seems inappropriate. Although there exist only a few case reports, large complex defects, such as limb–body–wall–complex and ectopia cordis should be detectable before 10 weeks. Even the early diagnosis of gastroschisis at 9 weeks has been described, in which the addition of colour Doppler was helpful .
Gastrointestinal and genitourinary anomalies
Most of congenital gastrointestinal anomalies are obstructive conditions of the gastrointestinal tract. Such anomalies are atresia, stenosis, and duplication of the gastro-intestinal tract, cysts or tumours, and hepatic, splenic, or pancreatic diseases. Alteration of the amniotic fluid amount owing to possible imbalance of production and resorption by the fetal gastrointestinal and urinary system do not become significant until the second trimester. The fluid that can be found in the embryonic stomach as early as 8 weeks does not present swallowed amniotic fluid, but originates probably from gastric secretion . Therefore, one cannot expect oligo- or polyhydramnios as markers for gastrointestinal or urogenital anomalies. Surprisingly, a case of oesophageal atresia showed increased fluid amount in the stomach and bowel at 10 weeks gestation, and first after 12 weeks, the typical feature of empty stomach occurred . As with the gastrointestinal tract, the development of the genitourinary tract is not complete before the post-embryonic period. Genitourinary tract anomalies are usually not detected before the 11–13+6 week scan. Gross anomalies, such as persistent cloaca, however, may present as large cystic areas in the lower abdomen. Diagnoses of gastrointestinal and genitourinary anomalies during the embryonic period have not been described.
Musculoskeletal anomalies, poly- and oligodactyly, limb defects
Many skeletal disorders can cause abnormal shape and size of the skeleton. The spectrum ranges from absence of a finger to the major lesions of the skeleton caused by amniotic adhesions. One limb may have reduced growth owing to vascular compromise, or general dwarfism caused by serious congenital osteochondro-dysplasia.
In severe anomalies, such as amniotic rupture sequence or limb-body-wall complex, the reduction defects of an extremity and the kyphoscoliosis may be easily detected at 9 weeks or even at the end of week 8. A sign for the diagnosis is the abnormal shape of the amniotic cavity, which, during 8 and 9 weeks, usually looks like a well-demarcated balloon with the embryo inside. Small anomalies, such as polydactyly, can be seen in Meckel–Gruber syndrome as demonstrated in an embryo of only 22 mm CRL . Caution must be practised with the diagnosis of polydactyly, as reflections of the ultrasound beam from both sides of fingers and toes may give the false impression of hexadactyly.
The normal embryonic and early fetal development of the skeleton has been described by ultrasound in a small study . Diagnosis of a rare skeletal dysplasia that might lead to the termination of a pregnancy must be based on reliable and unambiguous images. The size of the measured long bones in embryos and young fetuses are near the limit of the ultrasound resolution. Thus, improvements of the image quality will be necessary before accurate measurements can be made . In serious dysplasias, such as achondrogenesis, significant bone shortening may not be obvious before 11 weeks .
Conjoined twins is obviously an easy diagnosis during the embryonic period. Chen et al. presented a review of first-trimester diagnoses up to 2010. They identified reports of three cases at 7 weeks, five cases at 8 weeks, and 12 cases at 9 weeks .
Many cases of aneuploidy are missed during an early scan if they do not present obvious major structural abnormalities. Detectable differences have been found between euploid embryos and trisomies using biometric markers (e.g. CRL, heart rate, and yolk sac diameter); however, these deviations from the norm in embryonic heart rate in trisomies 13 and 18, and in yolk sac diameter in trisomy 21 pregnancies observed at 6–10 weeks, were small and unlikely to provide the basis for a method of screening . Examples of embryonic diagnoses made by transvaginal ultrasound before 10 weeks’ gestation are presented in Table 2 .
| Age | Crown–rump length (mm) | Earliest reported sonographic diagnosis | Earliest possible detection (weeks) |
|---|---|---|---|
| 7 weeks 0–6 days | 9–14 | Conjoined twins, three cases . | 6 |
| 8 weeks 0–6 days | 15–22 | Conjoined twins, five cases ; Spina bifida, one case . | 7 (?)– 8 |
| 9 weeks 0–6 days | 23–31 | Holoprosencephaly, four cases ; spina bifida, four cases ; acrania/anencephaly/exencephaly, two cases ; body stalk anomaly, one case ; ectopia cordis, one case ; polydactyly, two cases ; Meckel–Gruber syndrome, two cases ; gastroschisis, one case . | 7 7 (?)– 8 7 7–8 9 8–9 8–9 9 |
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